Obesity is a significant health problem. Obesity has reached epidemic proportions globally, and the World Health Organization estimates that there are more than 1 billion overweight adults (BMI of 25.0-29.9), of which at least 300 million are obese (BMI of 30 or above) (Kanavos et al. 2012; WHO). Obesity is associated with premature death through increasing the risk of many chronic diseases, including type 2 diabetes, cardiovascular disease, and certain cancers (Kopelman 2007; Guh et al. 2009). In addition, obesity is associated with respiratory difficulties, chronic musculoskeletal problems, lumbago, skin problems, and infertility (Brown et al. 2009). Most of the evidence proposing obesity-associated health problems has been obtained from epidemiological analyses of human subjects; the precise molecular mechanisms of obesity-associated health problems have not yet been determined (Kanasaki and Koya 2010). To better understand the underlying mechanisms of human disease, good animal models are essential. In addition, as the prevalence of obesity is rising with its socioeconomic consequences, the quest to find new treatments or a cure is also increasing. Pharmaceutical treatment is one avenue that has been pursued, but currently there are only a limited number of compounds on the market because many have failed or been withdrawn because of side effects (Nilsson et al. 2011). Given that the developmental process from initial idea to marketed product typically requires more than 10 years and the attrition rate is notably high, it is important that animal models used are good surrogates for human obesity. A number of obese rodent models (e.g. ob/ob, NZO, ZDF and diet-induced obesity (DIO)) are currently used for the discovery and preclinical testing of anti-obesity and anti-diabetic drugs (Kanasaki and Koya 2010). These obese rodent models have some similarities as well as some differences with obesity in humans. For example, most obese humans do not have leptin deficiency; instead, they have hyperleptinemia and leptin resistance and thus generally do not respond with weight loss during recombinant leptin treatment. This finding underlines the fact that although the ob/ob mouse is indeed a valuable and useful animal model of obesity, it does not reflect the complete background of obesity in humans and will therefore not always be predictive of the effect of pharmacological treatments in humans. Similarly, one of the drawbacks of the DIO rodent models is highly variable phenotype due to genetic background of the rodent species used. In addition, DIO models develop hyperinsulinemia but not always hyperglycemia, thereby making them good models for obesity but not necessarily for type 2 diabetes. Likewise, there are some advantages and disadvantages in other rodent models currently used in pre-clinical testing such as db/db mice, Zucker rats and NZO mice models.
Most of obese animal models currently used have been either selected through inbreeding or characterized following spontaneously arising mutations and are often associated with increased food intake (Shafrir and Ziv, 2009). Irrespective of the origin, obesity is characterized by increase in adipose tissue mass and involves corresponding changes in adipose tissue to synthesize and store excess fat. However, obese animal model based on primary alterations in adipose tissue independent of increase food intake or other defects is not available.
Thus, there is a tremendous need for obese animal models for preclinical testing that better mimic the development of obesity and type 2 diabetes in humans in order to better understand the molecular mechanisms of obesity and obesity-associated health problems.
WAT Mitochondria in Whole Body Energy Homeostasis:
A major role has been established for white adipose tissue (WAT) in regulating energy intake, energy expenditure, and insulin sensitivity (Guilherme et al. 2008; Kusminski and Scherer 2012). In addition, recent studies have highlighted the potential relevance of WAT mitochondria in the cellular physiology of the adipocyte and its impact on systemic metabolic regulation (Kusminski and Scherer 2012; De Pauw et al 2009). The adipocyte interprets nutritional and hormonal cues in its microenvironment, and then coordinates its mitochondrial response either to oxidize incoming fatty acid and carbohydrate fuels through the tricarboxylic acid cycle and the respiratory chain, or to store these fuels safely in the form of triglycerides until whole-body energy requirements signal for their release (Sun et al. 2011). Through their ability to influence key biochemical processes central to the adipocyte, such as fatty acid esterification and lipogenesis, as well as their impact upon the production and release of key adipokines, mitochondria play a crucial role in adipose tissue homeostasis and determining systemic insulin sensitivity (Kusminski and Scherer 2012; Rong et al. 2007; Wilson-Fritch et al. 2004). The synchronized initiation of adipogenesis and mitochondrial biogenesis indicates that mitochondria play a pertinent role in the differentiation and maturation of adipocytes (De Pauw et al 2009; Lu et al. 2010).
PHB in Mitochondrial Biology and Adipogenesis:
Prohibitin (PHB, also known as PHB1) is an evolutionarily conserved protein that functions as a mitochondrial chaperone and has a role in mitochondrial biogenesis (Merkwirth and Langer 2009). The PHB gene has been mapped to the chromosome17q12-q21 locus in humans (Sato et al. 1992). The locus 17q21 has been identified among chromosomal regions harboring genes influencing the propensity to store fat in the abdominal area in a genome-wide scan (Perusse et al. 2001). The siRNA-mediated knockdown of PHB in Caenorhabditis elegans results in significant reduction in intestinal fat content (Artal-Sanz and Tavernarakis 2009). In addition, using 3T3-L1 preadipocytes we have recently shown that PHB is an important target gene during adipogenesis (Ande et al. 2012). Overexpression of PHB in preadipocyte facilitates adipogenesis whereas silencing PHB has inhibitory effect on mitochondrial biogenesis and adipogenesis (Ande et al. 2012; Liu et al. 2012). In addition, we have shown that PHB inhibits insulin-stimulated fatty acid and glucose oxidation in adipose tissue, which is mediated through pyruvate carboxylase (Vessal et al. 2006), an important enzyme in de novo fatty acid synthesis and glyceroneogenesis (Jitrapakdee et al. 2006). Collectively, these evidences point towards a critical role of PHB in adipose tissue homeostasis.